Tear film disturbances account for eye symptoms in millions of Americans. At the present time, treatment primarily consists of replacing a defective tear film with artificial tear substitutes which are sold over-the-counter. The major limitation of these products is their short retention time in the eye. Patients must apply drops as often as every hour to obtain comfort from these products. Recent accomplishments have focused on developing aqueous solutions containing components which will stabilize the tear film or replace specific deficiencies.
A normal tear film is the product of: (1) aqueous secretion by the lacrimal gland and accessory lacrimal glands; (2) secretion of mucous primarily by the goblet cells of the conjunctiva; and (3) lipids secreted by the meibomian gland and the glands of Zeis and Moll in the lids. Mucin, the innermost layer (0.035 .mu.m), wets the lipophilic epithelial surface of the cornea with the middle aqueous layer. The aqueous layer (7 .mu.m) contains dissolved proteins, carbohydrates, glycoproteins, oxygen, and inorganic salts. The outer lipid layer (0.1 .mu.m) retards evaporation of the aqueous component.
Dry eye syndrome, or keratoconjuctivitis sicca (KCS), can occur secondarily to many autoimmune diseases, and as a result of abnormalities in the precorneal tear film physiology. Besides an awareness of a chronically irritable sore eye by the patient, clinicians can diagnose dry eye syndrome by various measurements. These include a tear breakup time of 10 seconds or less in the absence of blinking, or a Schirmer test value of 5 mm or less. The latter involves leaving a standard strip of filter paper under the lower lid for 5 minutes. Other measurements are also helpful and include an observation of a smaller than normal marginal tear strip upon slitlamp examination, and/or a positive rose bengal stain which detects the presence of precipitated mucin and devitalized cells.
The stimulation of aqueous tears by a drug acting on the autonomic nervous system is an approach that had in the past limited success via a systemic route and little success via a topical route of administration. For example, some ophthalmologists have recommended oral ingestion of very dilute solutions of the cholinergic, pilocarpoine, to stimulate tear secretion. However, unpleasant side effects have discouraged widespread use of ingested pilocarpine.
The stimulation of aqueous tears by the systemic or oral route has the undesirable side effect of causing systemic drug reactions by materials such as pilocarpine and other cholinergics. Moreover, by the time the active drug transfers itself through the body to the eye, its effect is significantly diluted. To date, there is no known effective composition for topical route of administration to pharmacologically treat dry eye syndrome.
As earlier indicated, the treatment with tear replacement compositions is not totally satisfactory because of their short retention time in the eye. Often the user of dry eye syndrome tear replacement products must continually apply drops even as often as every hour to obtain eye comfort. Moreover, especially for wearers of contact lenses, this problem of short time retention becomes quite real, rendering tear replacement products unsatisfactory. In short, sufferers of dry eye syndrome are currently, for all practical purposes, excluded from the possibility of wearing contact lenses, since those lenses and their effective use, to say nothing of their comfortable use, necessarily depends upon adequate tear production. Compounds of the earlier patent are indeed quite satisfactory. In fact, they are now in clinical trials. It has, however, been noted in some cases that the tertiary amine molecules of our earlier patent, when applied to the eye, may cause some stinging. Conventional wisdom leads one to the conclusion that the stinging, to the extent that it occurs, is related to the basic (alkaline) nature of the tertiary amines. It has, however, now been surprisingly discovered that tertiary amines, in conjunction with a cyclopropyl adduct, will decrease any stinging sensation, resulting in greater patient comfort and acceptance.
A primary objective of the present invention is to provide tear stimulants that are tertiary amine based which avoid patient eye stinging in those patients that have a tendency toward eye stinging sensation with tear stimulants involving tertiary amines.
Another general objective of the present invention is to provide cyclopropylvinylogous tertiary amine based tear stimulants.
And a still further objective of the present invention is to provide tear stimulants that have decreased side effects when compared to those in our original U.S. Pat. No. 4,820,737.
Another objective of the present invention is to provide a tear stimulant which can be directly applied topically to the eye to minimize side effects and which will stimulate tear production in the eye itself, as opposed to simply acting as a fluid lubricant.
A yet further objective of the present invention is to provide a tear stimulant which has all of the above advantages as enumerated in each of the objectives, and yet provides a sigma agonist component for release of proteins from the lacrimal acini that is at least equal in effectiveness to those mentioned in our earlier U.S. Pat. No. 4,820,737, but causes no eye stinging sensation.
The method and means of accomplishing each of these objectives, as well as others, will become apparent from the detailed description which follows.